TNF‑α increases inflammatory factor expression in synovial fibroblasts through the toll‑like receptor‑3‑mediated ERK/AKT signaling pathway in a mouse model of rheumatoid arthritis

Abstract

Osteoarthritis is a type of joint disease that may lead to other joint diseases. Previous research has demonstrated that tumor necrosis factor (TNF)‑α is associated with osteoarthritis activity and pathology. The possible mechanisms of the TNF‑α‑mediated signaling pathway have not been clearly elaborated in synovial fibroblasts. The present study aimed to investigate the potential mechanisms of TNF‑α in a mouse model of iodoacetate‑induced osteoarthritis. Reverse transcription‑quantitative polymerase chain reaction, ELISA, western blotting and immunohistochemistry were performed to evaluate the role of TNF‑α in the progression of osteoarthritis. The results revealed that the serum levels of TNF‑α, interleukin (IL)‑1β, IL‑4 and IL‑6 were significantly upregulated in a mouse model of iodoacetate‑induced osteoarthritis compared with healthy mice (P<0.01). TNF‑α, IL‑1β, IL‑4 and IL‑6 mRNA and protein levels were also significantly upregulated in synovial fibroblasts in the experimental mice (P<0.01). It was demonstrated that TNF‑α increased pro‑inflammation factors matrix metalloproteinase (MMP)‑3, MMP‑9, nuclear factor (NF)‑κB and receptor activator of NF‑κB ligand (RANKL) in synovial fibroblasts. It was also observed that the toll‑like receptor (TLR)‑3 was significantly upregulated and extracellular signal‑regulated kinase (ERK) and protein kinase B (AKT) were significantly downregulated in synovial fibroblasts in osteoarthritis mice (P<0.01). An in vitro assay demonstrated that TNF‑α inhibitor decreased mRNA and protein levels of IL‑1β, IL‑4 and IL‑6 in synovial fibroblasts. The knockdown of TLR‑3 abolished the TNF‑α upregulated mRNA and protein levels of IL‑1β, IL‑4 and IL‑6 in synovial fibroblasts. In addition, the knockdown of TLR‑3 also reversed TNF‑α‑upregulated ERK and AKT expression in synovial fibroblasts. In vivo assays demonstrated that TNF‑α inhibitor significantly decreased the deposition of IL‑1β, IL‑4 and IL‑6 as well as bone destruction and significantly increased the body weight and osteoarthritis score for osteoarthritic mice (P<0.01). TNF‑α inhibitor decreased TLR‑3 and significantly increased the expression and phosphorylation of ERK and AKT in articular cartilage (P<0.01). In conclusion the results of the present study indicate that TNF‑α serves an essential role in synovial fibroblasts in osteoarthritis, suggesting that inhibition of TNF‑α may decrease inflammation via the TLR‑3‑mediated ERK/AKT signaling pathway in a mouse model of monosodium iodoacetate‑induced osteoarthritis.

D-Lactate Increases Cytokine Production in Bovine Fibroblast-Like Synoviocytes via MCT1 Uptake and the MAPK, PI3K/Akt, and NFκB Pathways

“…Previously, we observed an increase in the infiltration of neutrophils and MMP-9 in the synovial fluid of cows with ARA [8]; however, in the synovial fluid of animals with ARA, the presence of IL-8 has not yet been detected. We demonstrate that bTNF-α, a well-known joint proinflammatory agent [12,[69][70][71], increases the production of IL-6 and IL-8 in bFLSs in a similar fashion to that described in hFLSs [72]. bTNF-α, but not D-lactate, increased the expression of CXCL-1 and CXCL-2.…”

An Integrative Pharmacology Model for Decoding the Underlying Therapeutic Mechanisms of Ermiao Powder for Rheumatoid Arthritis

“…The symptoms of RA, such as synovial tissue hyperplasia and articular cartilage tissue injury, can be relieved by inhibiting the MAPK signaling pathway ( Bao et al, 2018 ; Liu et al, 2018 ; Yang et al, 2018 ). The TNF signaling pathway is associated with osteoarthritis activity and pathology, including bone loss, osteoblasts proliferation, and inflammation ( Yu et al, 2018 ; Li et al, 2019 ; Jiang et al, 2020 ). The inhibition of the TNF signaling pathway can decrease inflammation and bone destruction ( Yu et al, 2018 ).…”

“…The TNF signaling pathway is associated with osteoarthritis activity and pathology, including bone loss, osteoblasts proliferation, and inflammation ( Yu et al, 2018 ; Li et al, 2019 ; Jiang et al, 2020 ). The inhibition of the TNF signaling pathway can decrease inflammation and bone destruction ( Yu et al, 2018 ). The NF-κB signaling pathway has been reported to be related to the pathogenesis of RA ( Xia et al, 2018 ).…”

Inhibitory role of long non‐coding RNA OIP5‐AS1 in rheumatoid arthritis progression through the microRNA‐448–paraoxonase 1–toll‐like receptor 3–nuclear factor κB axis

“…The TLRs–NF‐κB signalling pathways have been recognized to participate in RA pathogenesis, among which the roles of TLR4 have been largely investigated (Kim, Bang, Son, Baek, & Kim, 2018; Samarpita, Kim, Rasool, & Kim, 2020). Likewise, TLR3 up‐regulation and NF‐κB activation have been evidenced in synovial fibroblasts in a mouse model with RA (Yu, Xie, Jiang, Sun, & Huang, 2018). Engagement of TLR3 was also suggested to induce vascular endothelial growth factor and IL‐8 in human RA‐FLSs (Moon et al., 2010).…”